Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21].C([Li])CCC.[CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[O:30]>O1CCCC1>[CH3:19][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:29]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[OH:30])=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)[C:17]([CH3:18])=[CH:16][CH:15]=1
Reactant: O=Cc1ccncc1
Reactant: Cc1ccc(C)n1-c1ccc(Br)c(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc(C(O)c2ccncc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 12 mL of an anhydrous ether solution of 1.08 g (3.4 mmol) of 1-(4-bromo-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-pyrrole, 1.4 mL of n-butyllithium (a tetrahydrofuran solution, 2.44 M) was added at one time at −60° C. and the mixture solution was stirred for one hour. Then, 5 mL of a tetrahydrofuran solution of 350 mg (3.27 mmol) of 4-formylpyridine was added thereto at −60° C. and the mixture solution was stirred while raising the temperature to room temperature over one hour. The reaction solution was partitioned between a saturated ammonium chloride aqueous solution and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The obtained residue was purified by a silica gel column (n-hexane:ethyl acetate=1:1) to obtain 754 mg (66%) of a target product as a pale yellow oil.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CN(C)[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18].[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH3:18][C:17]1([CH3:19])[CH:27]([C:26]2[CH:29]=[CH:30][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH2:28][C:16]1=[O:20]
Reactant: CC(C)C(=O)N(C)C
Reactant: C=Cc1ccc(C)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1ccc(C2CC(=O)C2(C)C)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
Trifluoroacetic anhydride (25 g, 0.09 mol) was added portionwise over a period of 10 minutes at −10° C., to a solution of N,N-dimethyl-isobutyramide (9.16 g) in DCM (100 mL). The resulting mixture was stirred at −10° C. for 10 minutes and then a viscous solution of 4-methylstyrene (8.2 g) and collidine (11.9 mL) in DCM (15 mL) was added portionwise at −10° C. The resulting mixture was heated at reflux for 22 hours then cooled and concentrated under reduced pressure. The oil residue was washed with ethyl ether and the organic phase was decanted away. DCM (75 mL) and water (75 mL) were added to the oil and the mixture was heated at 100° C. for 6 hours. The mixture was cooled to room temperature, separated, and the aqueous layer was extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure to give 35 g of crude oil, which was purified by flash chromatography (5% to 50% of EtOAc in hexane) to give 6.45 g (50% yield) of 2,2-dimethyl-3-p-tolyl-cyclobutanone as a yellow oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.[NH2:29][NH2:30].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:20]([C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1)c1c(O)c2ccncc2n(-c2ccccc2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2ccncc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-phenylacetyl-1,7-naphthyridin-2(1H)-one (100 mg, 0.28 mmol) produced in Synthesis Example 26 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 68 μL), and the mixture was stirred at 100 to 110° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,7]naphthyridin-4(5H)-one (78 mg, 79%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]1[N:26]([C:27](=O)[CH2:28]Cl)[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=2[S:23][CH2:22]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][N:26]2[CH:21]([CH2:22][S:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=32)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1CSc2ccccc2N1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2c3ccccc3SCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
A 13.47 g (97.43 mmol) portion of potassium carbonate was added to DMF solution (360 ml) containing 11.59 g (32.48 mmol) of 3-(t-butoxycarbonyl)aminomethyl-4-chloroacetyl-3,4-dihydro-2H-1,4-benzthiazine and stirred at room temperature overnight and then at 60° C. for 3 hours. This was returned to room temperature, mixed with cool water and extracted with ethyl acetate. The extract was dried (Na2SO4) and then concentrated under a reduced pressure. The thus dried residue under a reduced pressure was dissolved in 180 ml of tetrahydrofuran and cooled to 0° C. This was mixed with 4.48 ml (48.72 mmol) of borane-dimethyl sulfide complex and stirred at 0° C. for 2 hours and then at room temperature for 2 hours. Cool water was added dropwise to the reaction solution which was subsequently stirred for 30 minutes and then extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and dried (Na2SO4), and then the solvent was removed by evaporation under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (650 cc; elution by ethyl acetate-hexane=1:4) and further recrystallized from ethyl acetate-hexane to obtain 5.04 g of the title compound (51% in yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].O.[C:26]([OH:30])(=[O:29])[CH:27]=O>C(#N)C.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:27]([C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:26]([OH:30])=[O:29])[CH:10]=[CH:9][C:8]=1[F:11])(=[O:6])[NH2:7]
Reactant: O=CC(=O)O
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: NC(=O)c1cc(N)ccc1F
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Temperature: 100 °C
Yield: 46 %

Procedure:
A mixture of 3-amino-6-fluorobenzamide (85 mg, 0.5 mmol), 3,4-dimethoxyphenylboronic acid (91 mg, 0.5 mmol) and glyoxylic acid monohydrate (46 mg, 0.5 mmol) in acetonitrile (2.0 mL) and DMF (0.2 mL) was heated at 100° C. for 20 min. in a microwave reactor. After removal of solvent, the crude was triturated with methylene chloride. The precipitate formed was collected by filtration and washed with methylene chloride to give 13A after drying, yield: 46%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.81 (s, 3H) 3.82 (s, 3H) 4.92 (s, 1H) 6.83-6.89 (m, 1 H) 6.93 (d, J=8.35 Hz, 1H) 6.96-7.02 (m, 1H) 7.03-7.07 (m, 1H) 7.10 (d, J=1.76 Hz, 1H) 7.15 (dd, J=5.93, 2.86 Hz, 1H), LCMS: 349 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[C@H:52]([NH:55][C:56](=[O:58])[CH3:57])[CH2:51]1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][C@H:52]([NH:55][C:56](=[O:58])[CH3:57])[CH2:51]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(=O)N[C@H]1CCNC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(=O)N[C@H]1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-N-(pyrrolidin-3-yl)acetamide. MS(m/e): 428.3 (MH+).
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=O)[CH:18]=[N:17]2)=[CH:13][CH:12]=1>C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21](=[O:23])[CH2:7][C:6]#[N:8])[CH:18]=[N:17]2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)CC#N)cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
According to Scheme 7, Step 1: At −78° C., BuLi (23 mmol, 9.2 mL, 2.5M) was added dropwise to a solution of acetonitrile (21.1 mmol, 0.87 g) in THF (25 mL). The resulting mixture was stirred at this temperature for 20 minutes and then ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (19.2 mmol, 5.00 g) in THF (25 mL) was added. The reaction mixture was stirred at −78° C. for 1 hour and then allowed to warm up to room temperature and stirred for another 1 hour. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (50 mL×3). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on combi-flash EtOAc/PE (1:15 to ˜1:5) to give 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile (13.1 mmol, 3.33 g, 68%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][N:9]2[C:23]([C:22]2[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:24])[CH2:4][CH2:3]1
Reactant: CN1CCC(C2=NCCc3ccsc32)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCc3ccsc3C2C2CCN(C)CC2)cc1
Yield: 90 %

Procedure:
7-(1-Methylpiperidin-4-yl)-4,5,-dihydrothieno[2,3-c]pyridine (0.1 g), 4-methoxybenzoyl chloride (0.086 g), and triethylamine (0.112 ml ) were reacted in toluene (5 ml) exactly as described in example 4. Yield 90% of crude [7-(1-Methylpiperidin-4-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl]-(4-methoxyphenyl)-methanone. MS: M+=370.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].CC(C)=O.O.C(=O)(O)[O-].[Na+].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)=[CH:31][C:27]=1[C:28](Cl)=[O:29]>C(OCC)(=O)C>[CH3:1][N:2]([CH2:3][C@H:4]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:6]=[CH2:7])[C:28](=[O:29])[C:27]1[CH:31]=[C:32]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)[CH:33]=[CH:34][C:26]=1[O:25][CH3:24]
Reactant: C=CC[C@H](CNC)c1ccccc1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC[C@H](CN(C)C(=O)c1cc(-n2cnnn2)ccc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine (S)-N-methyl-(2-phenylpent-4-enyl)amine (1.93 g, 11.0 mmol), acetone/water (4/1, 125 mL), and sodium bicarbonate (3.0 g, 35.5 mmol). Cool in an ice bath with vigorous stirring. Add portionwise, 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (2.86 g, 11.8 mmol). After the addition is complete, warm to ambient temperature. After 1.5 hours, evaporate in vacuo to remove most of the acetone. Extract the evaporated reaction mixture with ethyl acetate. Extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (S)-N-methyl-N-(2-phenylpent-4-enyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide: Rf=0.35 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C@@H:25]([CH2:27][OH:28])[CH3:26].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[OH:28][CH2:27][C@@H:25]([NH:24][C:21]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][O:10][CH:11]=2)=[CH:20][N:19]=1)=[O:23])[CH3:26]
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Reactant: C[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)NC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.8 %

Procedure:
To a solution of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (80 mg, 0.24 mmol) and D-alaninol (22.8 □L, 0.29 mmol) in THF (7 mL) was added 1-hydroxybenzotriazole hydrate (37.3 mg, 0.24 mmol), N-ethyldiisopropylamine (105.2 □L, 0.60 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (47.1 mg, 0.24 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 72 h. Then the reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=1:1 to 2:3) afforded the title product (39 mg, 42%) which was obtained as white solid. MS: m/e=389.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C1CCNCC1.CC=C(C)C.[C:37](Cl)(=[O:41])[CH2:38][CH2:39][CH3:40]>C(Cl)(Cl)Cl>[C:37]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)=[O:8])[CH2:25][CH2:24]1)(=[O:41])[CH2:38][CH2:39][CH3:40]
Reactant: CCCC(=O)Cl
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Agent: CC=C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CCCC(=O)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 24 h
Yield: 12.5 %

Procedure:
A small sample of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (60 mg, 0.16 mmol) was weigh d out in a 4 mL sealable vial, followed by (piperidinomethyl)polystyrene (0.12 g, 0.32 mmol). To this was added 10 mL of amylene-stabilized chloroform and butyryl chloride (18.0 μL, 0.17 mmol). The vial was capped and placed in a shaker, where it was kept at room temperature for 24 h, then at 50° C. for 36 h. The crude reaction mixture was then applied to a 2 g SCX column, washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo to a dry residue, which was purified by preparative thin layer chromatography. Elution with 9:1 dichloromethane-methanol provided the title compound (9 mg, 13%), isolated in 98% purity by HPLC analysis (Method C: gradient from 50% acetonitrile-50% water with 0.1% trifluoroacetic acid to 90% acetonitrile-10% water with 0.1% trifluoroacetic acid over 10 min; hold 2 min; back to 50% acetonitrile-10% water with 0.1% trifluoroacetic acid over 1 min; hold 2 min; 0.5 ml/min; Waters Symmetry Cl18, 3.5 μM column, 4.6 by 75 mm; 25° C.).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)C>O>[C:13]1([N:19]2[C:5](=[O:7])[CH:4]=[C:3]([C:2]([F:1])([F:11])[F:12])[NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]n1-c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 184 parts of ethyl trifluoroacetoacetate, 120 parts of phenylhydrazine, 200 parts by volume of ethanol and 20 parts by volume of 22° Be hydrochloric acid was heated under reflux, with stirring, for one hour, then 500 parts of water were added and the product was cooled in ice. The yellow precipitate obtained was filtered off, drained, washed, with a small portion of chilled toluene until decoloration took place. Thereafter it was dried in an oven (50° C.). 215 parts of 1-phenyl-3-trifluoromethyl-5-pyrazolone was obtained of which the melting point was 193° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[C:8](C(OC(C)(C)C)=O)[NH:9][C:10]=1[CH2:11][C:12]([OH:14])=[O:13])=[O:5])[CH3:2].FC(F)(F)C(O)=O.C(=O)=O.C(O)C.[OH-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:22])=[CH:8][NH:9][C:10]=1[CH2:11][C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CC(=O)O)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Temperature: -30 °C
Yield: 85.2 %

Procedure:
A solution of 5-carboxymethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (6.3 g, 20 mmol) in 600 ml of dichloromethane and trifluoroacetic acid (120 ml, 1.55 mol) was heated to reflux under a nitrogen atmosphere for 2.5 hours. The reaction mixture was stirred in the dry ice-ethanol bath and added with aqueous sodium hydroxide solution (1.55 mol sodium hydroxide in 100 ml of water) while maintaining the temperature at −30° C. Upon completion of the addition, the mixture was extracted with dichloromethane (100 ml×7). The combined organic extracts were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (3.6 g, 85.7%) as a white solid.
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=O)[NH:12][C:11]2=O.CO.Cl>C1COCC1.O>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11]2
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Brc1ccc2c(c1)CNC2
Temperature: 22 °C
Reaction time: 2 h

Procedure:
564.2 ml of a 1M borane/THF solution are added dropwise to 42.5 g (188 mmol) of 5-bromoisoindole-1,3-dione in 300 ml of THF (dry) at −5° C. over a period of 60 min. The mixture is subsequently stirred for 2 h at 22° C. and then for 16 h at 80° C. The mixture is then cooled to 0° C., before 200 ml of methanol (exothermic!) and 200 ml of 2M hydrochloric acid are slowly added. The resultant mixture is stirred for 3 h at 80° C., cooled to 22° C., and 100 ml of water are added. The aqueous solution is extracted three times with 150 ml of dichloromethane each time, dried over sodium sulfate, filtered and evaporated to dryness: 5-bromo-2,3-dihydro-1H-isoindole; yield 15.4 g of “13” (41.3%); MW 198.06; Rt 1.099 min (“polar” method).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Cl-:1].[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:5]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ccc(CCl)cc1
Solvent: Cc1ccccc1
Product: OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a solution of [4-(chloromethyl)phenyl]methanol (4.691 g, 29.96 mmol) in toluene (30 ml) was added triphenylphosphine (9.444 g, 36.01 mmol). The mixture was heated under reflux for 20 hrs, and cooled to room temperature. The precipitate was collected by filtration, and dried under reduced pressure to give [4-(hydroxymethyl)benzyl](triphenyl)phosphonium chloride (11.47 g, yield 91.4%) as a white solid.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[S:31](=[O:33])(=[O:32])[CH2:30][CH2:29][C:28]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:44]([CH3:51])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:39][CH:38]=3)=[O:35])=[CH:27][C:26]=2[CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:51][N:44]([CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:28]2[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[C:25]3[CH:24]=[CH:23][C:22]([C:6]4[O:7][C:8]5[C:14]([O:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:12]=[CH:11][C:9]=5[CH:10]=4)=[CH:52][C:26]=3[CH:27]=2)=[O:35])=[CH:38][CH:39]=1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOc1cccc2cc(OB([O-])[O-])oc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOc1cccc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)oc12
Reaction time: 0.5 h
Yield: 60 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 7-propoxy-benzofuran-2-yl borate (165 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(7-propoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 143) (213 mg).